U.S. Pat. Nos. 6,251,910 and 6,525,060 disclose a variety of triazolo[4,5-d]pyrimidine derivatives, processes for their preparation, pharmaceutical compositions comprising the derivatives, and method of use thereof. These compounds act as P2T (P2YADP or P2TAC) receptor antagonists and they are indicated for use in therapy as inhibitors of platelet activation, aggregation and degranulation, promoters of platelet disaggregation and anti-thrombotic agents. Among them, Ticagrelor, [1S-(1α,2α,3β(1S*,2R*),5β)]-3-[7-[2-(3,4-difluorophenyl)cyclopropyl]amino]-5-(propylthio)-3H-1,2,3-triazolo[4,5-d]pyrimidin-3-yl)-5-(2-hydroxyethoxy)-cyclopentane-1,2-diol, acts as Adenosine uptake inhibitor, Platelet aggregation inhibitor, P2Y12 purinoceptor antagonist and Coagulation inhibitor. It is indicated for the treatment of thrombosis, angina, Ischemic heart diseases and coronary artery diseases. Ticagrelor is represented by the following structural formula I:

Ticagrelor is the first reversibly binding oral adenosine diphosphate (ADP) receptor antagonist and is chemically distinct from thienopyridine compounds like clopidogrel. It selectively inhibits P2Y12, a key target receptor for ADP. ADP receptor blockade inhibits the action of platelets in the blood, reducing recurrent thrombotic events. The drug has shown a statistically significant primary efficacy against the widely prescribed clopidogrel (Plavix) in the prevention of cardiovascular (CV) events including myocardial infarction (heart attacks), stroke, and cardiovascular death in patients with ACS.
Various processes for the preparation of ticagrelor, its enantiomers and related compounds, and their pharmaceutically acceptable salts are disclosed in U.S. Pat. Nos. 6,251,910; 6,525,060; 6,974,868; 7,067,663; and 7,250,419; U.S. Patent application Nos. 2007/0265282 and 2008/0214812; and European Patent Nos. EP0996621 and EP1135391; and PCT Publication Nos. WO2008/018823 and WO2010/030224.
In the preparation of ticagrelor or a pharmaceutically acceptable salt thereof, 4,6-dichloro-5-nitro-2-(propylthio)pyrimidine of formula II:

is a key intermediate. According to U.S. Pat. No. 5,654,285, the 4,6-dichloro-5-nitro-2-(propylthio)pyrimidine of formula II is prepared by adding propyl iodide to a solution of 4,6-dihydroxy-2-mercaptopyrimidine in potassium hydroxide; the resulting mixture is stirred for 4 days followed by acidifying the solution to pH 2-3 to produce 2-propylthio-pyrimidine-4,6-diol; which is then reacted with excess fuming nitric acid to produce 5-nitro-2-propylthiopyrimidine-4,6-diol. The 5-nitro-2-propylthiopyrimidine-4,6-diol is reacted with phosphoryl chloride in the presence of N,N-diethylaniline at reflux to produce a reaction mass, followed by concentrating to half volume and pouring onto ice to yield a black tar. The tar is extracted with ether to afford a solution, which is then dried and evaporated. The residue is chromatographed (SiO2, light petrol) to produce 4,6-dichloro-5-nitro-2-(propylthio)pyrimidine.
According to U.S. Pat. No. 5,747,496, the 4,6-dichloro-5-nitro-2-(propylthio)pyrimidine of formula II is prepared by adding propyl iodide to a suspension of 4,6-dihydroxy-2-mercaptopyrimidine in water containing sodium hydroxide; the reaction mixture is stirred for 2 weeks and then the reaction mass is concentrated to half volume; followed by the addition of hydrochloric acid and isolating the product by filtration to produce 2-propylthio-pyrimidine-4,6-diol. The 2-propylthio-pyrimidine-4,6-diol is then reacted with excess fuming nitric acid to produce 5-nitro-2-propylthiopyrimidine-4,6-diol. The 5-nitro-2-propylthiopyrimidine-4,6-diol is reacted with phosphoryl chloride in the presence of N,N-dimethylaniline at reflux to produce a reaction mass. The cooled reaction mass is poured onto ice followed by extracting with diethyl ether to afford a solution; then the combined extracts are dried and concentrated. The residue is chromatographed (SiO2, light petrol) to produce 4,6-dichloro-5-nitro-2-(propylthio)pyrimidine.
According to U.S. Pat. No. 6,525,060, ticagrelor is prepared by the condensation of 4,6-dichloro-5-nitro-2-(propylthio)pyrimidine with [3aR-(3aα,4α,6α,6aα)]-6-amino-tetrahydro-2,2-dimethyl-4H-cyclopenta-1,3-dioxol-4-ol, hydrochloride salt in the presence of N,N-diisopropylethylamine in tetrahydrofuran to produce [3aR-(3aα,4α,6α,6aα)]-6-[[6-chloro-5-nitro-2-(propylthio)-pyrimidin-4-yl]amino]-tetrahydro-2,2-dimethyl-4H-cyclopenta-1,3-dioxol-4-ol, followed by reduction in the presence of iron powder in acetic acid to produce [3aR-(3aα,4α,6α,6aα)]-6-[[5-amino-6-chloro-2-(propylthio)-pyrimidin-4-yl]amino]-tetrahydro-2,2-dimethyl-4H-cyclopenta-1,3-dioxol-4-ol, which is then reacted with isoamyl nitrite in acetonitrile to produce [3aR-(3aα,4α,6α,6aα)]-6-[7-chloro-5-(propylthio)-3H-1,2,3-triazolo[4,5-d]-pyrimidin-3-yl]tetrahydro-2,2-dimethyl-4H-cyclopenta-1,3-dioxol-4-ol. The resulting triazolo[4,5-d]-pyrimidin compound is reacted with ammonia in tetrahydrofuran to produce [3aR-(3aα,4α,6α,6aα)]-6-[7-amino-5-(propylthio)-3H-1,2,3-triazolo[4,5-d]-pyrimidin-3-yl]tetrahydro-2,2-dimethyl-4H-cyclopenta-1,3-dioxol-4-ol, which is then reacted with a solution of trifluoromethanesulfonyloxy-acetic acid methyl ester in tetrahydrofuran in the presence of butyllithium to produce [3aR-(3aα,4α,6α,6aα)]-6-[[7-amino-5-(propylthio)-3H-1,2,3-triazolo[4,5-d]-pyrimidin-3-yl]tetrahydro-2,2-dimethyl-4H-cyclopenta-1,3-dioxol-4-ol]oxy]acetic acid methyl ester, followed by bromination in the presence of isoamylnitrite in bromoform to produce [3aR-(3aα,4α,6α,6aα)]-6-[[7-bromo-5-(propylthio)-3H-1,2,3-triazolo[4,5-d]-pyrimidin-3-yl]tetrahydro-2,2-dimethyl-4H-cyclopenta-1,3-dioxol-4-ol]oxy]acetic acid methyl ester. The resulting bromo compound is then reacted with (1R-trans)-2-(3,4-difluorophenyl)cyclopropanamine [R—(R*,R*)]-2,3-dihydroxybutanedioate (1:1) salt in the presence of N,N-diisopropylethylamine in dichloromethane to produce [3aR-[3aα,4α,6α(1R*,2S*),6aα]]-[[6-[7-[[2-(3,4-difluorophenyl)cyclopropyl]amino]-5-(propylthio)-3H-1,2,3-triazolo[4,5-d]-pyrimidin-3-yl]tetrahydro-2,2-dimethyl-4H-cyclopenta-1,3-dioxol-4-ol]oxy]acetic acid methyl ester, followed by reaction with DIBAL-H in tetrahydrofuran to produce [3aR-[3aα,4α,6α(1R*,2S*),6aα]]-[[6-[7-[[2-(3,4-difluorophenyl)cyclopropyl]amino]-5-(propylthio)-3H-1,2,3-triazolo[4,5-d]-pyrimidin-3-yl]tetrahydro-2,2-dimethyl-4H-cyclopenta-1,3-dioxol-4-ol]oxy]-ethanol, which is then treated with trifluoroacetic acid in water to produce [1S-(1α,2α,3β(1S*,2R*),5β)]-3-[7-[2-(3,4-difluorophenyl)cyclopropyl]amino]-5-(propylthio)-3H-1,2,3-triazolo[4,5-d]pyrimidin-3-yl)-5-(2-hydroxyethoxy)-cyclopentane-1,2-diol (ticagrelor).
The processes for the preparation of 4,6-dichloro-5-nitro-2-(propylthio)pyrimidine of formula II disclosed in the above mentioned prior art have the following disadvantages and limitations:                a) longer reaction times, low yields and low purities of the products;        b) the time required for the alkylation reaction is from about 4 days to about 2 weeks, which is industrially not feasible;        c) the alkylation reaction reported in the prior art results in low yields and low purity of the product;        d) the use of excess nitric acid leads to the formation of nitration products;        e) the purity of the 5-nitro-2-propylthiopyrimidine-4,6-diol obtained in nitration is low and the color of the product is very dark;        f) the processes require large volumes of water to quench excess nitric acid on an industrial scale;        g) the processes involve the use of excess phosphorus oxychloride in the chlorination reaction;        h) the processes involve the use of N,N-dimethyl or N,N-diethyl aniline in the chlorination reaction, which are toxic and dangerous to environment; and        i) the overall process generates a large quantity of chemical waste which is difficult to treat.        
Based on the aforementioned drawbacks, the prior art processes have been found to be unsuitable for the preparation of 4,6-dichloro-5-nitro-2-(propylthio)pyrimidine of formula II at lab scale and in commercial scale operations.
A need remains for an improved and commercially viable process of preparing 4,6-dichloro-5-nitro-2-(propylthio)pyrimidine of formula II with high yields and purity, to resolve the problems associated with the processes described in the prior art, and that will be suitable for large-scale preparation. Desirable process properties include non-hazardous conditions, environmentally friendly and easy to handle reagents, reduced reaction times, reduced cost, greater simplicity, increased purity, and increased yield of the product, thereby enabling the production of Ticagrelor and its pharmaceutically acceptable acid addition salts in high purity and in high yield.